Bone formation is a multistep process mediated by the osteoblast and a variety of circulating endocrine factors in addition to local non- hormonal substances which function to control osteoblast growth and differentiation via paracrine and autocrine modes. It has been well- established that hormonal and non-hormonal effects on osteogenesis are mediated by signals which are transmitted from the outside to the inside of cells in the response to ligand binding, which stimulates second messengers and the ultimate transcription of those genes essential to coordinate the growth and differentiation of the osteoblast. Biological signals can also be transmitted from the inside of cells modulating the binding affinity of cell adhesion molecules as well as between cells via gap junctions. In fact early observations which demonstrated that bone cells can adhere to a variety of extracellular matrix substrates (ECM) have now been extended to reveal that a variety of integrins are expressed by osteoblasts, and that the integrin-ECM interaction is a required, immediate event in the transduction of biological signals which condition the osteoblast response to trophic factors. Moreover, cell adhesions molecules (CAMs) have also been identified in osteoblasts during embryogenesis. Consequently, we plan to pursue the hypothesis that cell-cell and cell-matrix contact are essential for the transduction of those biological events which are essential to initiate and modulate the orderly sequential expression of osteoblastic traits. To achieve this goal we will analyze the expression and synthesis of cell matrix (integrins) and CAMs in human and rodent osteoblastic cell lines as well as in normal primary cultures. Our experiments are all designed to analyze the mechanism by which cell adhesion molecules regulate osteoblast differentiation utilizing osteoprogenitor marrow stromal cell populations and specific biological markers of the phenotypic expression of osteoblast differentiation. The effects of calcitropic hormones and other osteotropic factors on the expression and function of the CAMs will be evaluated, as well as the correlation between the regulation of osteoblast differentiation by osteotrophic factors and their effect on cell-cell contact. Results of these studies should provide important insight into those regulatory processes which are essential for osteoblast differentiation into bone forming (mineralizing) cells, and thus facilitate potential exploitation of these properties for the stimulation of osteoblastic development and function in vitro or osteogenesis in vivo.